Human Astrocytes Transfer Aggregated Alpha-Synuclein via Tunneling Nanotubes
Open accessAbstract
Many lines of evidence suggest that the Parkinson's disease (PD)-related protein α-synuclein (α-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess α-SYN oligomers results in α-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances. The stressed astrocytes respond by conspicuously sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes, which in return deliver mitochondria, indicating a TNT-mediated rescue mechanism. Using a pharmacological approach to inhibit TNT formation, we abolished the transfer of both α-SYN and mitochondria. Together, our results highlight the role of astrocytes in α-SYN cell-to-cell transfer, identifying possible pathophysiological events in the PD brain that could be of therapeutic relevance. SIGNIFICANCE STATEMENT Astrocytes are the major cell type in the brain, yet their role in Parkinson's disease progression remains elusive. Here, we show that human astrocytes actively transfer aggregated α-synuclein (α-SYN) to healthy astrocytes via direct contact and tunneling nanotubes (TNTs), rather than degrade it. The astrocytes engulf large amounts of oligomeric α-SYN that are subsequently stored in the trans-Golgi network region. The accumulation of α-SYN in the astrocytes affects their lysosomal machinery and induces mitochondrial damage. The stressed astrocytes respond by sending out TNTs, enabling intercellular transfer of α-SYN to healthy astrocytes. Our findings highlight an unexpected role of astrocytes in the propagation of α-SYN pathology via TNTs, revealing astrocytes as a potential target for therapeutic intervention.
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In the AD and PD brain, both astrocytes and microglia acquire reactive, inflammatory phenotypes and can effectively phagocytose aggregated proteins and cell debris, as well as secrete various cytokines and inflammatory mediators.
“In the AD and PD brain, both astrocytes and microglia acquire reactive, inflammatory phenotypes and can effectively phagocytose aggregated proteins and cell debris, as well as secrete various cytokines and inflammatory mediators [8–13].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Introduction (page not provided) says reactive astrocytes engulf dead cells and aggregates of amyloid β and α-synuclein, and that astrocytes can produce cytokines and chemokines. The paper does not establish the corresponding inflammatory, phagocytic, and secretory claims for microglia in both AD and PD brains. (LLM, conf=0.88)
Experimental — accuracy not yet measuredStressed astrocytes respond by sending out tunneling nanotubes (TNTs), enabling intercellular transfer of pathogenic protein aggregates, as well as MHCII complexes to nearby cells.
“Subsequently, stressed astrocytes respond by sending out tunneling nanotubes (TNTs), enabling intercellular transfer of pathogenic protein aggregates, as well as MHCII complexes to nearby cells [11, 24].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Discussion states that stressed astrocytes send out TNTs that transfer aggregated α-synuclein to healthy astrocytes. The cited paper does not report TNT-mediated transfer of MHCII complexes, so that part of the sentence is unsupported by this source. No page numbers are provided in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe concentrations of αSYN-F and Aβ-F used were selected based on previous studies.
“The concentrations were selected based on our previous studies [11, 12, 23, 28, 29].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Materials and Methods section says the 0.5 μM α-SYN exposure concentration was chosen based on previous investigations. It does not establish that the Aβ-F concentration was selected on that basis, so this source supports only the α-SYN part of the claim. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe αSYN and Aβ accumulation result in severe cellular stress, indicated by lysosomal and mitochondrial deficiencies.
“The αSYN and Aβ accumulation result in severe cellular stress, indicated by lysosomal and mitochondrial deficiencies [11, 12, 23].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Results section reports mitochondrial defects after α-SYN oligomer exposure in human astrocytes, and the Discussion says α-SYN accumulation disrupts lysosomal machinery and is stressful to the cells. The cited paper does not establish the same effects for Aβ accumulation. Page numbers are not available in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredAstrocytes easily degrade αSYN and Aβ monomers, while they accumulate larger oligomers and fibrils.
“These observations are in line with our previous discoveries that astrocytes easily degrade αSYN and Aβ monomers, while they accumulate larger oligomers and fibrils [11, 12].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Results section (page not provided) reports that human astrocytes rapidly degraded α-SYN monomers but retained α-SYN oligomers over six days. The Discussion also reports long-term storage of aggregated Aβ42. This paper does not establish degradation of Aβ monomers or accumulation of fibrils by astrocytes. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Astrocytes are capable of transferring αSYN as well as MHCII to other astrocytes via direct membrane contact and through TNTs.
“Our previous results indicate that astrocytes are capable of transferring αSYN as well as MHCII to other astrocytes via direct membrane contact and through TNTs, implicating astrocytes as one of the important players in propagation of αSYN pathology [11, 24].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Results section, “TNTs contribute to α-SYN transmission” (page unavailable), reports transfer of α-SYN between astrocytes through direct contact and TNTs. The cited paper does not report transfer of MHCII, so that part of the attributed claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMicroglia and astrocytes are responsible for many inflammatory processes in affected brains, including phagocytosis of αSYN and Aβ aggregates, secretion of inflammatory mediators, and stimulation of the innate immune system.
“Microglia and astrocytes are known to be responsible for many inflammatory processes in affected brains, including phagocytosis of αSYN and Aβ aggregates, secretion of inflammatory mediators, and stimulation of the innate immune system [8–12].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Introduction reports that reactive astrocytes engulf Aβ and α-SYN aggregates and produce cytokines and chemokines. The paper does not establish the same activities for microglia or say that these cells stimulate the innate immune system; its Discussion instead mentions possible astrocyte involvement in T-cell activation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAstrocytes accumulate large amounts of αSYN and Aβ aggregates, resulting in severe cellular stress.
“We have previously shown that astrocytes accumulate large amounts of αSYN and Aβ aggregates, resulting in severe cellular stress [11, 12, 23, 24].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
The Discussion (page not provided) says that α-SYN accumulates in astrocytes and causes substantial cellular stress. It also reports that astrocytes engulf and store large amounts of aggregated Aβ42, but does not say that Aβ accumulation causes the stress described here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCultured astrocytes accumulate αSYN and Aβ aggregates but not the monomeric form of the proteins.
“We have previously reported that cultured astrocytes accumulate αSYN and Aβ aggregates but not the monomeric form of the proteins [11, 12].”
From Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates (2021) · cites this paper as [11]
αSyn has the ability to spread via astrocyte-to-neuron transfer via tunneling nanotubes.
“iii) αSyn has the ability to spread to adjacent cells via secretion in exosomes [209], uptake via endocytosis [210] and cell-surface receptors like HSPGs, or even direct neuron-to-neuron [211, 212] or astrocyte-to-neuron [213] transfer via tunneling nanotubes (Fig. 2).”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [213]
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Bayati, A., & McPherson, P. S. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107742 · Cited by 46 · see citing works
Alpha-synuclein and the prion hypothesis in Parkinson's disease
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Prionoid Proteins in the Pathogenesis of Neurodegenerative Diseases
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Tunneling Nanotubes Facilitate Intercellular Protein Transfer and Cell Networks Function
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Self-citationAstrocytic uptake of neuronal corpses promotes cell‐to‐cell spreading of tau pathology
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Enteroendocrine cells: the gatekeepers of microbiome-gut-brain communication
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Selective Neuronal Death in Neurodegenerative Diseases: The Ongoing Mystery.
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Astrocytes: The Stars in Neurodegeneration?
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- Authors
- Rostami, J., Holmqvist, S., Lindström, V., Sigvardson, J., Westermark, G. T., Ingelsson, M., Bergström, J., Roybon, L., & Erlandsson, A.
- Affiliations
- Uppsala University (SE)
- Lund University (SE)
- Corresponding author
- Erlandsson, Anna
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-10-31
- Volume
- 37
- Issue
- 49
- Pages
- 11835-11853
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5719970
- OpenAlex
- W2765364382
- Cited by
- 339
- References
- 75
- Citations by year
- 2026: 45 · 2025: 30 · 2024: 64 · 2023: 47 · 2022: 34 · 2021: 38 · 2020: 26 · 2019: 31 · 2018: 24
- FWCI
- 15.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Åke Wiberg Stiftelse
- Innovationsfonden
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- alpha-synuclein, Parkinson's disease, tunneling nanotubes, astrocytes, prion-like propagation, intercellular transfer, lysosomal degradation, trans-Golgi network, mitochondrial damage, endoplasmic reticulum stress, mitochondrial transfer
- MeSH terms
- Astrocytes, Cell Communication, Cells, Cultured, Humans, Nanotubes, alpha-Synuclein, Embryonic Stem Cells
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